Renal Carcinoma: The VHL Gene. We have identified the tumor suppressor gene for the familial form of kidney cancer associated with von Hippel Lindau disease and have shown that the VHL gene is the kidney cancer tumor suppressor gene. Mutational analysis of this conserved gene identified germline mutations in the VHL gene in affected individuals from 100/114 kindreds resulting in amino acid deletions, frameshift and/or other changes. A correlation has been identified between the location and type of VHL mutations and the phenotype of the disease. This provides a method for early diagnosis of at-risk or affected individuals. We have demonstrated that the VHL gene is a critical, gene for kidney cancer. The discovery of VHL mutations in a majority of localized as well as advanced renal carcinomas indicates that the VHL gene plays a critical role in the origin of both sporadic and hereditary kidney cancer. In characterizing the biochemical function of the VHL gene we have recently shown that the B and C regulatory subunits of the cellular transcription factor Elongin (SIII) are targets of the VHL protein. These findings reveal an important transcriptional regulatory network and suggest that the VHL protein may function as a key regulator of this network, with its ultimate target the RNA polymerase II elongation complex. We have recently demonstrated that there is a tightly regulated, cell-density dependent transport of VHL into and/or out of the nucleus. We have identified the localization signals for the VHL protein to move to the nucleus and for retention in the nucleus and shown that the VHL protein regulates VEGF expression in post-transcriptional manner. Papillary Renal Carcinoma. We have described a new hereditary cancer syndrome, Hereditary Papillary Renal Cell Carcinoma (HPRC). Affected individuals develop multifocal, bilateral papillary RCC. We have evaluated families with this autosomal dominant familial cancer syndrome and have localized the gene to a specfic chromosomal area. We have identified a candidate gene in the area of interest and have detected both germline and somatic mutations of the gene. We have developed a new molecular genetically based classification for papillary renal carcinoma and have identified candidate genes for both types. Prostate carcinoma. A program designed to identify tumor suppressor genes that are involved in the developoment and/or progression of prostate cancer is underway. Loss of heterozygosity studies are being performed on matched samples of normal and tumor DNA to map regions of the genome that are frequently lost during tumor development. A region from the short arm of chromosome 8 (8p22) has been shown to be lost frequently in prostate tumors as well as prostate intraepithelial neoplasia (PIN). Candidate cDNAs are being cloned from this region to be evaluated as potential tumor suppressor genes. The significance of this project lies in the identification of the tumor suppressor genes associated with kidney and prostate cancer as well as in the evaluation and development of new agents for use in therapy of patients with these neoplasms.